Antibiotics LL-Z1272 identified as novel inhibitors discriminating bacterial and mitochondrial quinol oxidases
Antibiotics LL-Z1272 identified as novel inhibitors discriminating bacterial and mitochondrial quinol oxidases
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DOI：
10.1016/j.bbabio.2008.11.016
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发表时间：
2009-02-01
影响因子：
4.3
通讯作者：
Kita, Kiyoshi
中科院分区：
文献类型：
--
作者：
Mogi, Tatsushi;Ui, Hideaki;Kita, Kiyoshi
为了对抗耐药细菌，我们用细菌醌醇氧化酶筛选了北里生命科学研究所化学图书馆，这种氧化酶不存在于线粒体呼吸链中。我们确定了五个异戊二烯基苯酚，LL-Z1272 β，γ，δ，β和ζ，作为大肠杆菌细胞色素bd的新抑制剂。我们发现这些化合物也能抑制E.大肠杆菌BO型泛醇氧化酶和锥虫交替氧化酶，尽管这三种氧化酶在结构上不相关。LL-Z1272 β和β（脱氯衍生物）对细胞色素bd的活性更高，而LL-Z1272 γ、δ和ζ（氯化衍生物）是细胞色素bo和锥虫交替氧化酶的强效抑制剂。因此，异戊烯基酚是有用的选择性抑制醌醇氧化酶和了解呼吸醌醇氧化酶的分子机制作为探针的醌醇氧化位点。由于哺乳动物线粒体中不存在醌醇氧化酶，因此对人类细胞毒性较小的LL-Z1272 β和δ可用作开发针对病原菌和非洲锥虫的新型化疗剂的先导化合物。(C)2008 Elsevier B. V.保留所有权利。
To counter antibiotic-resistant bacteria, we screened the Kitasato Institute for Life Sciences Chemical Library with bacterial quinol oxidase, which does not exist in the mitochondrial respiratory chain. We identified five prenylphenols, LL-Z1272 beta, gamma, delta, epsilon and zeta, as new inhibitors for the Escherichia coli cytochrome bd. We found that these compounds also inhibited the E. coli bo-type ubiquinol oxidase and trypanosome alternative oxidase, although these three oxidases are structurally unrelated. LL-Z1272 beta and epsilon (dechlorinated derivatives) were more active against cytochrome bd while LL-Z1272 gamma, delta, and zeta (chlorinated derivatives) were potent inhibitors of cytochrome bo and trypanosome alternative oxidase. Thus prenylphenols are useful for the selective inhibition of quinol oxidases and for understanding the molecular mechanisms of respiratory quinol oxidases as a probe for the quinol oxidation site. Since quinol oxidases are absent from mammalian mitochondria, LL-Z1272 beta and delta, which are less toxic to human cells, could be used as lead compounds for development of novel chemotherapeutic agents against pathogenic bacteria and African trypanosomiasis. (C) 2008 Elsevier B.V. All rights reserved.